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Hum. Reprod. Advance Access published online on August 25, 2005
Human Reproduction, doi:10.1093/humrep/dei260
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
Received April 28, 2005
Revised July 4, 2005
Accepted July 18, 2005

Article

Estradiol supplementation modulates neuroendocrine response to M-chlorophenylpiperazine in menstrual status migrainosus triggered by oral contraception-free interval

R.E. Nappi 1, G. Sances 2, B. Brundu 3, S. De taddei 3, A. Sommacal 3, N. Ghiotto 2, F. Polatti 4, and G. Nappi 5*

1 Research Centre for Reproductive Medicine, University of Pavia; Department of Obstetrics and Gynaecology, IRCCS ‘San Matteo’, University of Pavia; University Centre of Adaptive Disorders and Headache (UCADH), University of Pavia
2 University Centre of Adaptive Disorders and Headache (UCADH), University of Pavia; Headache Centre, IRCCS ‘C.Mondino Foundation’, Department of Neurology, Rome, Italy
3 Department of Obstetrics and Gynaecology, IRCCS ‘San Matteo’, University of Pavia
4 Research Centre for Reproductive Medicine, University of Pavia
5 University Centre of Adaptive Disorders and Headache (UCADH), University of Pavia; Chair of Neurology, University ‘La Sapienza’, Rome, Italy

* To whom correspondence should be addressed.
G. Nappi, E-mail: renappi{at}tin.it


  Abstract

BACKGROUND: Migraine triggered by oral contraception (OC)-free interval is very common and may be extremely severe, long-lasting and poorly responsive to analgesics (status migrainosus). The serotoninergic (5-HT) system is crucially involved in pain threshold and it is sensitive to estradiol (E2). Therefore, we aimed to assess neuroendocrine correlates of OC status migrainosus in response to the direct central 5-HT agonist meta-chlorophenylpiperazine (m-CPP) and to test the effect of transdermal E2 supplementation of the OC-free interval. METHODS: Clinical investigative protocol, single-blinded placebo-controlled treatment. Oral m-CPP (0.5 mg/kg body weight) challenge test was performed in 10 patients with status migrainosus occurring within 48 h of the discontinuation of a monophasic pill (30 µg of ethinyl estradiol and 150 µg of desogestrel) and in six healthy women assuming the same OC as controls. In a consecutive menstrual cycle, patients with OC status migrainosus underwent to the same test after they were blindly treated with 2.0 g of percutaneous E2 gel or placebo daily during the pill-free interval. Plasma prolactin and cortisol levels and clinical characteristics of migraine attacks were evaluated. RESULTS: Women with OC-status migrainosus showed a derangement of prolactin release (F = 4.8; P < 0.01) and a lack of cortisol response (F = 5.8; P < 0.001) after m-CPP in comparison with controls. Transdermal E2 during the pill-free interval significantly restored prolactin (F = 2.8; P < 0.01) and cortisol responses (F = 18.9; P < 0.001) against placebo and positively affected the duration (P < 0.001), the number of hours in which pain intensity prohibits daily activity (P < 0.001), the episodes of vomiting (P < 0.001) and the consumption of analgesics (P < 0.001). CONCLUSIONS: Status migrainosus triggered by OC-free interval is associated with impaired prolactin and cortisol responses following m-CPP challenge. Transdermal E2 supplementation is able to restore neuroendocrine response to this specific 5-HT agent, exerting a positive clinical effect on the course of menstrually related migraine.

Keywords: estradiol/meta-chlorophenylpiperazine test/oral contraception/pill-free interval/status migrainosus.
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